Dihexa (N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide): Research, Mechanism & Current Evidence

What is Dihexa -aminohexanoic amide)?

Dihexa is a small synthetic molecule derived from angiotensin IV, developed at Washington State University. Despite frequently being described as a peptide, it is heavily modified and behaves more like a small-molecule drug.

It has not been studied in humans. A related clinical-stage compound, fosgonimeton, was developed by Athira Pharma and reached trials in Alzheimer's disease.

Status: Preclinical. No human studies published.

What is Dihexa -aminohexanoic amide) researched for?

Synaptogenesis — the formation of new connections between neurons — in rodent models of cognitive impairment.

Alzheimer's and Parkinson's disease models.

• Improvements in spatial, working, and consolidation demonstrated across animal models.
• Enhanced acquisition through increased synaptic plasticity.
• Restoration in impairment models including scopolamine-induced amnesia.
• Reduced amyloid burden in Alzheimer's models.
• Decreased neuroinflammation and glial activation.
• Protection of synapses in neurodegeneration models.
• 3-fold increase in dendritic spine formation demonstrated.
• Increases brain-derived neurotrophic factor expression.
• Promotes new blood vessel formation in brain.

How does Dihexa -aminohexanoic amide) work?

Dihexa is reported to act through hepatocyte growth factor and its receptor c-Met, a signalling pair involved in tissue growth and, in the brain, in forming synapses.

The frequently repeated claim that it is millions of times more potent than BDNF comes from a specific in-vitro assay of synapse formation. Potency in a dish measures how little is needed to produce an effect in that assay; it is not a statement about clinical usefulness.

Reported targets: c-Met

What does the research show?

Rodent studies report restored cognitive performance in impairment models. Cell studies support the synaptogenesis mechanism.

Fosgonimeton, the clinical-stage relative, did not meet its primary endpoint in its Alzheimer's trial — the most directly relevant human evidence available for this mechanism.

Limitations of the current evidence

There is no human data on Dihexa itself.

Promoting growth-factor signalling raises theoretical concerns about unwanted cell growth that have not been addressed in long-term studies.

The BDNF potency comparison is routinely quoted out of its original in-vitro context.

References

1. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents

   McCoy AT, Benoist CC, Wright JW, et al. · The Journal of pharmacology and experimental therapeutics · 2013

   Oral dihexa (2 mg/kg) completely reversed scopolamine-induced cognitive deficits in Morris water maze by day 7; produced near 3-fold increase in hippocampal dendritic spines at picomolar concentrations.

   PMID 23055539

2. AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway

   Sun X, Deng Y, Fu X, et al. · Brain sciences · 2021

   Dihexa restored spatial learning in APP/PS1 Alzheimer's mice, increased neuronal cells and synaptophysin expression, decreased astrocyte/microglia activation, and reduced IL-1B and TNF-a via PI3K/AKT pathway.

   Animal study · PMID 34827486

3. The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system

   Benoist CC, Kawas LH, Zhu M, et al. · The Journal of pharmacology and experimental therapeutics · 2014

   Dihexa binds HGF with high affinity (Kd = 65 pM), induces c-Met phosphorylation and hippocampal spinogenesis/synaptogenesis similar to HGF; effects blocked by c-Met inhibitor confirming HGF/c-Met dependence.

   PMID 25187433

4. The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases

   Wright JW, Kawas LH, Harding JW · Progress in neurobiology · 2015

   Comprehensive review establishing dihexa as an orally active, BBB-permeable compound that facilitates compromised memory and motor systems via HGF/c-Met modulation.

   Review or meta-analysis · PMID 25455861

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